Monoclonal antibodies selectively bind tumor cell differentiation antigens in vitro and in vivo. Since natural effector mechanisms often do not mediate killing of monoclonal antibody bound cells we have devised methods of linking extremely toxic proteins to the antibodies to selectively kill tumor cells. We have succeeded in developing several new approaches to apply immunotoxins in vivo. (1) Cloning toxins, then altering their structure at the gene level to decrease non target cell toxicity; (2) intrathecal administration of immunotoxins for therapy of brain tumors that kill 2-5 logs of tumor cells in animal models; (3) preparation of genetically engineered immunotoxins for clinical trials of human brain tumor patients; (4) prevention of an immune response against immunotoxin with anti-CD4 antibodies; (5) specific deletion of Purkinje cells in rats, guinea pigs, and rhesus monkeys; (6) use of human cytotoxic proteins such as RNase linked to antibodies to selectively target cells; and (7) understanding the mechanism of human RNase neurotoxins.